Abstract Cigarette smoking is the leading cause of disease and preventable death in the United States. Cigarette smoking alone accounts for approximately 440,000 deaths annually, including primary contributions to heart and pulmonary disease, stroke, cancer, reproductive complications, and exacerbation of other pervasive health concerns. Quitting smoking is the number one behavior modification that promises to mitigate the onset of disease and prolong life. We will recruit smokers with a desire to quit, and ask them to use electronic cigarettes (e-cigarettes) for 16 weeks. After randomization, some will receive e-cigarettes with nicotine, and some will receive e-cigarettes without nicotine. A separate non-smoking group will serve as a control. We will test the hypothesis that heart rate variability will increase, sympathetic activity will be lower, and arterial stiffness will decrease in subjects who inhale vapor without nicotine, but that these responses will not change in subjects who inhale vapor containing nicotine. We will also address the influence of vaporized nicotine on the cerebrovasculature. Autonomic neural regulation of the circulation is linked with autoregulation of the cerebrovasculature, and smoking is linked with probabilities of having a cerebrovascular accident. We therefore will record cerebral blood velocities from the middle cerebral artery using transcranial Doppler ultrasound. Autoregulation will be assessed in the frequency domain by calculating the coherence and transfer function between mean arterial pressure and mean cerebral blood velocity. We will test the hypothesis that cerebral autoregulation will improve in subjects who quit smoking and inhale vapor containing no nicotine for eight weeks, and cerebral autoregulation will not change in subjects who quit smoking but continue to inhale nicotine. This study is innovative, in that we will not only study the influence of quitting smoking and transitioning to e- cigarettes over the course of 16 weeks, but we will also study the acute impact of inhaling vaporized nicotine on vagal and sympathetic activities during inhalation. Such acute observations have not been made, but will help to inform regulatory policies and decisions associated with vaporized nicotine.